F on: Fluorotriorganosilyl‐derivatized Tyr3‐octreotate was labeled with 18F− providing the first practical formulation in 18F‐radiochemistry for the labeling of a peptide (see scheme). The very mild reaction conditions and the fast labeling make this strategy a valuable tool for the synthesis of 18F‐radiopharmaceuticals.

We aimed to evaluate 68 Ga-DOTATATE PET/CT for the early prediction of time to progression and clinical outcome after a first cycle of peptide receptor radionuclide treatment (PRRT) in a cohort of patients with well-differentiated neuroendocrine tumors. Methods: Thirty-three consecutive patients (22 men and 11 women; mean age 6 SD, 57.8 6 12.1 y) were investigated at baseline and again 3 mo after initiation of the first cycle of PRRT. 68 Ga-DOTATATE receptor expression was assessed using 2 measures of standardized uptake value (SUV): maximum SUV (SUV max ) and tumor-to-spleen SUV ratio (SUV T/S ). Percentage change in SUV scores after PRRT relative to baseline (DSUV) was calculated. After completing 1-3 cycles of PRRT, patients entered the follow-up study, for estimation of time to progression. According to the Response Evaluation Criteria in Solid Tumors, progression was defined on the basis of contrast-enhanced CT. Clinical symptoms, as well as the tumor markers chromogranin A and neuron-specific enolase, were also recorded during regular follow-up visits. Results: The 23 of 31 patients with decreased SUV T/S after the first PRRT cycle had longer progression-free survival than did the 8 of 31 patients with stable or increased scores (median survival not reached vs. 6 mo, P 5 0.002). For the 18 of 33 patients showing a reduction in SUV max , there was no significant difference in progression-free survival (median survival not reached vs. 14 mo, P 5 0.22). Multivariate regression analysis identified SUV T/S as the only independent predictor for tumor progression during follow-up. In the 17 of 33 patients with clinical symptoms before PRRT, DSUV T/S correlated with clinical improvement (r 5 0.52, P , 0.05), whereas DSUV max did not (r 5 0.42, P 5 0.10). Changes in the tumor markers (chromogranin A and neuronspecific enolase) did not predict DSUV scores, clinical improvement, or time to progression. Conclusion: Decreased 68 Ga-DOTATATE uptake in tumors after the first cycle of PRRT predicted time to progression and correlated with an improvement in clinical symptoms among patients with welldifferentiated neuroendocrine tumors; DSUV T/S was superior to DSUV max for prediction of outcome.

Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, 68 Ga and 18 F stand out because of the ease of radionuclide introduction (e.g., 68 Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the 18 F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible 18 F-SiFA-and 18 F-SiFAlin-(SiFA 5 silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard 68 Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors. Methods: SiFA-and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried 18 F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard 68 Ga-DOTATATE. Results: Synthetically easily accessible 18 F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than 68 Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for 68 Ga-DOTATATE. Conclusion: The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumorto-background ratios although lower than those observed with 68 Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for 18 F-labeled peptides advantageous for routine clinical application.

The syntheses of different (18)F-labeled peptides using the highly effective labeling synthon p-(di- tert-butylfluorosilyl) benzaldehyde ([ (18)F]SiFA-A) for the development of (18)F-radiopharmaceuticals for oncological positron emission tomography (PET) is reported. The novel and mild labeling technique for the radiosynthesis of [ (18)F]SiFA-A, based on an unexpectedly efficient isotopic (19)F- (18)F exchange, yielded the (18)F-synthon [ (18)F]SiFA-A in almost quantitative yields in high specific activities between 225 and 680 GBq/micromol (6081-18 378 Ci/mmol) without applying HPLC purification. The [ (18)F]SiFA-A was finally used to label the N-terminal amino-oxy (N-AO) derivatized peptides AO-Tyr (3)-octreotate (AO-TATE), cyclo(fK(AO-N)RGD and N-AO-PEG 2-[D-Tyr-Gln-Trp-Ala-Val-betaAla-His-Thi-Nle-NH 2] (AO-BZH3, a bombesin derivative) in high radiochemical yields. Density functional theory (DFT) calculations confirmed high efficiency of the isotopic exchange, which is predicted to proceed via a pentacoordinate siliconate intermediate dissociating immediately to form the radiolabeled [ (18)F]SiFA-A.

In this study silica- and alkoxysilane-coated ultrasmall superparamagnetic iron oxide (USPIO) particles were synthesized, and their ability to label immortalized progenitor cells for magnetic resonance imaging (MRI) was compared. USPIO particles were synthesized by coprecipitation of ferric and ferrous salts. Subsequently, the particles were coated with silica, (3-aminopropyl)trimethoxysilane (APTMS), and [N-(2-aminoethyl)-3-aminopropyl]trimethoxysilane (AEAPTMS). The size of the USPIO particles was about 10 nm without a significant increase in diameter after coating. The highest T2 relaxivity was achieved for silica-coated USPIO particles, 339.80 +/- 0.22 s-1 mM-1, as compared with APTMS- and AEAPTMS-coated ones, reaching 134.40 +/- 0.01 and 84.79 +/- 0.02 s-1 mM-1, respectively. No toxic effects on the cells could be detected by trypan blue, TUNEL, and MTS assays. Uptake of USPIO particles was evaluated by Prussian blue staining, transmission electron microscopy, T2-MR relaxometry, and mass spectrometry. It was found that cell uptake of the different USPIO particles increased for longer incubation times and higher doses. Maximum cellular iron concentrations of 42.1 +/- 4.0 pg/cell (silica-coated USPIO particles), 37.1 +/- 3.5 pg/cell (APTMS-coated USPIO particles), and 32.7 +/- 4.0 pg/cell (AEAPTMS-coated USPIO particles) were achieved after incubation of the cells with USPIO particles at a dose of 3 micromol/mL for 6 h. The decrease of the T2 relaxation time of the cell pellets was most pronounced for cells incubated with silica-coated USPIO particles followed by APTMS- and AEAPTMS-coated particles, respectively. In gelatin gels even small clusters of labeled cells were detected by 1.5 T MRI, and significant changes in the T2 relaxation times of the gels were determined for 10000 labeled cells/mL for all particles. In summary, as compared with APTMS- and AEAPTMS-coated particles, silica-coated USPIO particles provide the highest T2 relaxivity and most effectively reduce the T2 relaxation time of immortalized progenitor cells after internalization. This suggests silica-coated USPIO particles are most suited for cell labeling approaches in MRI.

It is known that small HBED-CC/antibody ratios are prerequisites for minimal interference of labels with antigen-binding domains. Here, the coupling of about one HBED-CC per antibody proved to be sufficient for efficient (68)Ga labeling, pointing to the successful application of (68)Ga for molecular imaging with small recombinant proteins.

The progression of b-amyloid deposition in the brains of mice overexpressing Swedish mutant b-amyloid precursor protein (APPSwe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel b-amyloid tracer 18 Fflorbetaben. Methods: Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of 18 F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BP ND ) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of b-amyloid plaque load. Results: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BP ND based on the entire dynamic emission recordings. 18 F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P , 0.01) in cortical 18 F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P , 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P , 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R 5 0.95, P , 0.001). Conclusion: In the first longitudinal PET study in an AD mouse model using the novel b-amyloid tracer 18 F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.

In this study (68)Ga-DOTA-TATE PET proved clearly superior to (18)F-DOPA PET for detection and staging of NET. (18)F-DOPA uptake tended to be increased in those patients with elevated plasma serotonin. We conclude that (18)F-DOPA PET should be employed in patients with NET with negative (68)Ga-DOTA-TATE PET and elevated plasma serotonin.